About this program
Avdoralimab / IPH5401 is a therapeutic antibody that specifically binds and blocks C5a receptors (C5aR) expressed on subsets of myeloid-derived suppressor cells (MDSC) and neutrophils. Part of the innate immune system, these types of cells promote tumor growth by secreting inflammatory and angiogenic factors. They potently suppress T and NK cells and hamper the activities of PD-1 checkpoint blockers.
C5a, a factor in the complement cascade, is often overexpressed in tumors, where it attracts and activates MDSC and neutrophils in the tumor microenvironment.
Avdoralimab is a fully human antibody that blocks the binding of C5a to C5aR, thereby reducing the accumulation and activation of MDSC and neutrophils in tumors. Treatment with avdoralimab may unleash anti-tumor activities of T cells and NK cells. Preclinical experiments support development of avdoralimab as single agent and in combination with PD-1 checkpoint blockers or other cancer immunotherapies.
Mechanism of action of avdoralimab
In January 2018, Innate Pharma and AstraZeneca entered into a clinical trial collaboration to evaluate the safety and efficacy of the combination of avdoralimab (anti-C5aR) and durvalumab (anti-PD-L1) in a Phase I study for patients with selected solid tumors.
The trial, called STELLAR-001*, started in September 2018.
*STELLAR = SelecTivE bLocking of compLement receptor C5AR to boost immune response and improve cancer outcomes
The dose escalation part of the trial STELLAR-001 is expected to establish a recommended dose regimen of avdoralimab in combination with durvalumab in selected solid tumors. The extension cohort part will assess the safety and efficacy of the combination in patients with non-small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC) - about 40 patients per indication.
At the European Society for Medical Oncology (ESMO) 2019 Congress, Innate presented encouraging data from the dose-escalation study (n=14). The combination of avdoralimab and durvalumab was well tolerated. Early activity signals were observed in hepatocarcinoma (HCC) and non-small cell lung cancer (NSCLC) patients.
As provided by the protocol, expansion cohorts of this trial were initiated in:
- Patients with IO-pretreated NSCLC
- Patients with IO-naïve HCC
- Patients with IO-pretreated HCC patients
Clinical trial sites are located in France and the US. For more information on the STELLAR-001 clinical study (NCT03665129), please visit clinicaltrials.gov.
C5a has been implicated in the pathogenesis of ARDS by promoting a proinflammatory environment, through the attraction of neutrophils and stimulation of immune cells such as T and B cells to release cytokines. Avdoralimab blocks C5aR and has the potential to reduce the inflammatory response in the lungs.
End of April 2020, Innate Pharma announced that the first patient was dosed in a randomized, double-blind Phase II clinical trial, evaluating the safety and efficacy of avdoralimab in COVID-19 patients with severe pneumonia.
The trial, named FORCE (FOR COVID-19 Elimination) will be conducted in La Timone Hospital and Nord Hospital in Marseille (Hopitaux Universitaires de Marseille – AP-HM) and in the Hospital Laveran (HIA-Laveran).
The trial is expected to enroll a total of 108 patients (age 18-80) between two cohorts: one cohort of COVID-19 patients with severe pneumonia without acute respiratory distress syndrome (ARDS) at baseline and one cohort of COVID-19 patients with severe pneumonia complicated by ARDS and admitted in ICU at baseline. In each cohort, patients will receive avdoralimab or placebo.
The Phase II trial is supported by an exploratory translational study, EXPLORE COVID-19, which suggests that patients who progress towards severe COVID-19 disease exhibit an activation of the C5a/C5aR pathway.
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